This NIH-supported research program has the long-term objective of elucidating the mechanisms and neuroplastic processes underlying acute and chronic dental and orofacial pain conditions and their control. Our recent data indicate that stimulation of the tooth pulp with an inflammatory irritant induces a NMDA receptor(NMDAR)-dependent 'central sensitization'of nociceptive neurons in the rat brainstem and thalamus and that the brainstem subnucleus caudalis ('medullary dorsal horn') is strategically involved in this process that has been implicated in the allodynia, hyperalgesia and spread and referral of pain that may occur after injury and inflammation. Purinergic receptor (P2XR) mechanisms have been recently identified as another modulatory process in spinal nociceptive transmission that may function through a powerful presynaptic regulation of glutamate release in the spinal dorsal horn. Recently, we have provided the first findings of a role for purinergic mechanisms in central nociceptive processing in the orofacial region. We propose to build upon these findings and use immunocytochemical and in vivo and in vitro electrophysiological techniques to test the hypotheses A) Afferent inputs to Vc from tooth pulp and dura include P2XR-expressing afferents that are sufficient to induce Vc central sensitization and associated sensorimotor behavior by central P2XR mechanisms;and B) Central P2XR produce a presynaptic facilitation of primary afferent transmission in Vc that is dependent on specific NMDAR subunits. Our experimental design will allow us to determine the afferents expressing P2XR, if these afferent inputs to brainstem are sufficient to induce central sensitization by central P2XR mechanisms, and if central P2XR presynaptically facilitate primary afferent transmission and act via NMDAR subunits. These studies will provide new information on a novel chemical mediator of nociceptive transmission, and new insights will be gained of the processing of sensory information from the tooth pulp and dura. These insights could be important in the development of improved therapeutic approaches for the prevention of pain associated with pulpal inflammation and for the relief of pain once it has been initiated.